Research & Scholarship

Clinical Trials

RATIONALE: Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different
ways to stop the growth of cancer cells, either by killing the cells or by stopping them from
dividing. Pravastatin may stop the growth of cancer cells by blocking some of the enzymes
needed for cell growth. Pravastatin may also help idarubicin and cytarabine work better by
making cancer cells more sensitive to the drugs. Giving idarubicin and cytarabine together
with pravastatin may kill more cancer cells.
PURPOSE: This phase II trial is studying how well giving idarubicin and cytarabine together
with pravastatin works in treating patients with relapsed acute myeloid leukemia.

Stanford is currently not accepting patients for this trial.For more information, please contact Joselene Sipin-Sayno, 650-736-8113.

This phase II trial is studying the side effects of giving combination chemotherapy together
with or without donor stem cell transplant and to see how well it works in treating patients
with acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop
the growth of cancer cells, either by killing the cells or by stopping them from dividing.
Giving more than one drug (combination chemotherapy) may kill more cancer cells. Giving
chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the
growth of cancer cells. It also stops the patient's immune system from rejecting the donor's
stem cells. The donated stem cells may replace the patient's immune cells and help destroy
any remaining cancer cells (graft-versus-tumor effect).

Stanford is currently not accepting patients for this trial.For more information, please contact Vani Jain, (650) 725 - 5459.

The purpose of this study is to evaluate the efficacy and safety of idelalisib in patients
with previously treated indolent Non-Hodgkin Lymphoma (iNHL) that is refractory both to
rituximab and to alkylating-agent-containing chemotherapy. The primary objective will be to
assess the overall response rate.
Eligible patients will initiate oral therapy with idelalisib at a starting dose of 150 mg
taken twice per day. Treatment with idelalisib can continue in compliant patients as long as
the study is still ongoing and the patients appear to be benefiting from treatment with
acceptable safety.

Stanford is currently not accepting patients for this trial.For more information, please contact Tessa St.Rose, (650) 736 - 4032.

Recent reports have identified a specific oncogenic mutation L265P of the MYD88 gene in
approximately 90% of the patients with Waldenström's macroglobulinemia. MYD88 is a key linker
protein in the signaling pathway of Toll Like Receptors (TLRs) 7, 8, and 9, and IMO-8400 is
an oligonucleotide specifically designed to inhibit TLRs 7,8, and 9. The scientific
hypothesis for use of IMO-8400 to treat patients with Waldenström's macroglobulinemia depends
on the inhibition of mutant MYD88 signaling in the TLR pathway, thereby interrupting the
proliferation of cell populations responsible for the propagation of the disease.

Stanford is currently not accepting patients for this trial.For more information, please contact Sipra Choudhury, 650-736-2563.

This phase I trial studies the side effects and best dose of inotuzumab ozogamicin when given
together with combination chemotherapy in treating patients with relapsed or refractory acute
leukemia. Immunotoxins, such as inotuzumab ozogamicin, can find cancer cells that express
cluster of differentiation (CD)22 and kill them without harming normal cells. Drugs used in
chemotherapy, such as cyclophosphamide, vincristine sulfate, and prednisone, work in
different ways to stop the growth of cancer cells, either by killing the cells or by stopping
them from dividing. Giving inotuzumab ozogamicin together with combination chemotherapy may
kill more cancer cells.

Stanford is currently not accepting patients for this trial.For more information, please contact Kevin Morrison, 650-725-5450.

This randomized phase III trial studies rituximab with bendamustine hydrochloride or
ibrutinib to see how well they work compared to ibrutinib alone in treating older patients
with previously untreated chronic lymphocytic leukemia. Monoclonal antibodies, such as
rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used
in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the
growth of cancer cells, either by killing the cells, by stopping them from dividing, or by
stopping them from spreading. Ibrutinib may stop the growth of cancer cells by blocking some
of the enzymes needed for cell growth. It is not yet known whether rituximab with
bendamustine hydrochloride may work better than rituximab and ibrutinib or ibrutinib alone in
treating chronic lymphocytic leukemia.

Stanford is currently not accepting patients for this trial.For more information, please contact Kevin Morrison, 650-725-5459.

This randomized phase III trial studies combination chemotherapy with blinatumomab to see how
well it works compared to induction chemotherapy alone in treating patients with newly
diagnosed breakpoint cluster region (BCR)-c-abl oncogene 1, non-receptor tyrosine kinase
(ABL)-negative B lineage acute lymphoblastic leukemia. Drugs used in chemotherapy work in
different ways to stop the growth of cancer cells, either by killing the cells, by stopping
them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as
blinatumomab, may block cancer growth in different ways by targeting certain cells. It is not
yet known whether combination chemotherapy is more effective with or without blinatumomab in
treating newly diagnosed acute lymphoblastic leukemia.

This phase II trial studies how well giving brentuximab vedotin together with combination
chemotherapy works in treating older patients with previously untreated stage II-IV Hodgkin
lymphoma (HL). Monoclonal antibody-drug conjugates, such as brentuximab vedotin, can block
cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such
as doxorubicin hydrochloride, vinblastine, and dacarbazine (AVD), work in different ways to
stop the growth of cancer cells, either by killing the cells or by stopping them from
dividing. Giving brentuximab vedotin, doxorubicin hydrochloride, vinblastine, and dacarbazine
together may kill more cancer cells.

Stanford is currently not accepting patients for this trial.For more information, please contact Tessa Hapanowicz, 650-721-0273.

An Extension Study for Subjects Who Are Deriving Benefit With Idelalisib (GS-1101; CAL-101) Following Completion of a Prior Idelalisib StudyNot Recruiting

This is a long-term safety extension study of idelalisib (GS-1101; CAL-101) in patients with
hematologic malignancies who complete other idelalisib studies. It provides the opportunity
for patients to continue treatment as long as the patient is deriving clinical benefit.
Patients will be followed according to the standard of care as appropriate for their type of
cancer. The dose of idelalisib will generally be the same as the dose that was administered
at the end of the prior study, but may be titrated up to improve clinical response or down
for toxicity. Patients will be withdrawn from the study if they develop progressive disease,
unacceptable toxicity related to idelalisib, or if they no longer derive clinical benefit in
the opinion of the investigator.

Stanford is currently not accepting patients for this trial.For more information, please contact Nini Estevez, 650-725-4041.

An Open Label Treatment Use Protocol for Ibrutinib in Subjects With Relapsed or Refractory Mantle Cell LymphomaNot Recruiting

The purpose of this study is to provide patients who have relapsed or refractory Mantle Cell
Lymphoma (MCL) with early access to an investigational medication called ibrutinib
(PCI-32765) and to collect safety information about the drug.

Stanford is currently not accepting patients for this trial.For more information, please contact Sipra Choudhury, 650-736-2563.

Efficacy and Safety of Idelalisib (GS-1101) in Combination With Bendamustine and Rituximab for Previously Treated Indolent Non-Hodgkin LymphomasNot Recruiting

The primary objective of this study is to evaluate the addition of idelalisib to
bendamustine/rituximab on progression-free survival (PFS) in adults with previously treated
indolent non-Hodgkin lymphoma (iNHL).
An increased rate of deaths and serious adverse events (SAEs) among participants with
front-line chronic lymphocytic leukemia (CLL) and early-line iNHL treated with idelalisib in
combination with standard therapies was observed by the independent data monitoring committee
(DMC) during regular review of 3 Gilead Phase 3 studies. Gilead reviewed the unblinded data
and terminated this study in agreement with the DMC recommendation and in consultation with
the US Food and Drug Administration (FDA).

Stanford is currently not accepting patients for this trial.For more information, please contact Lori Richards, 650-725-8589.

ECHELON-2: A Comparison of Brentuximab Vedotin and CHP With Standard-of-care CHOP in the Treatment of Patients With CD30-positive Mature T-cell LymphomasNot Recruiting

This is a double-blind, randomized, multicenter, phase 3 clinical trial to compare the
efficacy and safety of brentuximab vedotin in combination with CHP with the standard-of-care
CHOP in patients with CD30-positive mature T-cell lymphomas.

Stanford is currently not accepting patients for this trial.For more information, please contact Sipra Choudhury, 650-736-2563.

A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Refractory or Relapsed Lymphoid MalignanciesNot Recruiting

The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of
AGS67E both without and with myeloid growth factor (GF) in subjects with refractory or
relapsed lymphoid malignancies. Immunogenicity and anticancer activity of AGS67E will also be
assessed.

Stanford is currently not accepting patients for this trial.For more information, please contact Sipra Choudhury, 650-736-2563.

The purpose of this study is to determine the safety and effectiveness of pracinostat when
combined with azacitadine for patients who are 65 years of age or older and have Acute
Myelogenous Leukemia (AML)

Stanford is currently not accepting patients for this trial.For more information, please contact Leilani Hong Lien, 650-725-0437.

This pilot phase I/II trial studies the side effects and best of dose ipilimumab when given
together with local radiation therapy and to see how well it works in treating patients with
recurrent melanoma, non-Hodgkin lymphoma, colon, or rectal cancer. Monoclonal antibodies,
such as ipilimumab, can block cancer growth in different ways. Some block the ability of
cancer cells to grow and spread. Others find cancer cells and help kill them or carry
cancer-killing substances to them. Radiation therapy uses high energy x rays to kill cancer
cells. Giving monoclonal antibody therapy together with radiation therapy may be an effective
treatment for melanoma, non-Hodgkin lymphoma, colon, or rectal cancer

Stanford is currently not accepting patients for this trial.For more information, please contact Erin Waller, 650-725-0379.

The purpose of this study is to compare the outcomes across the 4 different treatment groups.
The investigators hope that this treatment will improve the ability to cure more patients
with HL and also limit the long-term side effects from the treatment. Although eliminating
radiation in cohort 4 will eliminate the risk for long-term side effects from radiation, it
is also possible that with BV+AVD chemotherapy alone there may be an increased risk of the
Hodgkin lymphoma coming back after initial treatment.

For patients with lymphoma that recurs after chemotherapy, bone marrow transplantation using
cells from a healthy donor represents potentially curative treatment. In these individuals,
cure is possible because transplantation of healthy donor immune cells can fight the lymphoma
in the patient. The goal of this work is to test a strategy that activates the healthy donor
immune cells so that they more effectively fight lymphoma and can result in an increased cure
rate for these patients. Our group has previously studied CpG, an immune activating
medication, in patients with lymphoma and demonstrated modest anti-tumor responses. We now
have a more potent form of CpG which we intend to test to see if it will better activate the
donor immune cells and result in shrinkage of tumor throughout the entire body, not just at
the injected site.

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals, 650-723-0822.

A Phase 1 Study to Investigate the Safety and Tolerability of REGN1979 in Patients With CD20+ B-Cell MalignanciesRecruiting

This is an open-label, multi-center, dose escalation study of REGN1979 administered as an IV
(intravenous) infusion. This phase 1 study will investigate the safety and tolerability of
REGN1979 in patients with Non-Hodgkin's Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)

This is a study of pembrolizumab (MK-3475) for participants with relapsed/refractory
classical Hodgkin Lymphoma (RRcHL) who: 1) have failed to achieve a response or progressed
after autologous stem cell transplant (auto-SCT) and have relapsed after treatment with or
failed to respond to brentuximab vedotin (BV) post auto-SCT or 2) were unable to achieve a
Complete Response (CR) or Partial Response (PR) to salvage chemotherapy and did not receive
auto-SCT, but have relapsed after treatment with or failed to respond to BV or 3) have failed
to achieve a response to or progressed after auto-SCT and have not received BV post auto-SCT.
The primary study hypothesis is that treatment with single agent pembrolizumab will result in
a clinically meaningful overall response rate.

Study of Tipifarnib in Subjects With Relapsed or Refractory Peripheral T-Cell LymphomaRecruiting

This Phase II studyis designed to investigate the antitumor activity in terms of objective
response rate (ORR) of tipifarnib in 18 subjects with advanced Peripheral T-Cell Lymphoma
(PTCL). The total number of patients could be extended to 30 pending on the degree of
response observed at an interim analysis. Tipifarnib will be administered until disease
progression then followed approximately every 12 weeks for survival until either death or 12
months after accrual of the last study subject, whichever occurs first.

This phase II trial studies how well nivolumab and brentuximab vedotin work in treating older
patients with untreated Hodgkin lymphoma. Monoclonal antibodies, such as nivolumab, may block
cancer growth in different ways by targeting certain cells. Biological therapies, such as
brentuximab vedotin, use substances made from living organisms that may stimulate or suppress
the immune system in different ways and stop cancer cells from growing. Nivolumab and
brentuximab vedotin may work better in treating older patients with untreated Hodgkin
lymphoma.

This study will test an experimental combination of the drugs Mylotarg and 5-azacitidine in
the hopes of finding a treatment that may be effective against Acute Myeloid Leukemia that
has come back after treatment.

Stanford is currently not accepting patients for this trial.For more information, please contact Jack Taw, (650) 723 - 2781.

A Study of GDC-0853 in Patients With Resistant B-Cell Lymphoma or Chronic Lymphocytic Leukemia.Not Recruiting

This open-label, Phase I study will evaluate the safety, tolerability, and pharmacokinetics
of increasing doses of GDC-0853 in patients with relapsed or refractory B-cell non-Hodgkin's
lymphoma or chronic lymphocytic leukemia. In a dose-expansion part, GDC-0853 will be assessed
in subsets of patients.

Stanford is currently not accepting patients for this trial.For more information, please contact Sabata Lund, 650-725-6432.

Trial of Hu5F9-G4 in Combination With Rituximab in Relapsed/Refractory B-cell Non-Hodgkin's LymphomaRecruiting

This Phase 1b/2 trial will evaluate Hu5F9-G4 in combination with rituximab. Hu5F9-G4 is a
monoclonal antibody which is designed to block a protein called CD47, which is widely
expressed on human cancer cells. Blocking CD47 with Hu5F9-G4 may enable the body's immune
system to find and destroy the cancer cells. Rituximab is a monoclonal antibody drug that is
used for treatment of non-Hodgkin's lymphoma and other types of cancer.
The major aims of the trial are: (Phase 1b) to investigate the safety and tolerability of
sequential dose cohorts and to determine a recommended Phase 2 dose for Hu5F9-G4 in
combination with rituximab, and (Phase 2) to evaluate the efficacy of Hu5F9-G4 in combination
with rituximab in patients with indolent lymphoma or diffuse large B-cell lymphoma as
measured by the overall response rate.

A Study Being Conducted at Multiple Locations to Compare Safety and Efficacy of Three Different Regimens; (1) High-Dose Lenalidomide; (2) Lenalidomide + Azacitidine; or (3) Azacitidine in Subjects ≥ 65 Years With Newly-Diagnosed Acute Myeloid LeukemiaNot Recruiting

The study aim is to compare safety and efficacy of high-dose lenalidomide regimen, sequential
azacitidine and lenalidomide and an azacitidine in persons ≥65 years with newly-diagnosed
acute myeloid leukemia (AML).

Stanford is currently not accepting patients for this trial.For more information, please contact Jack Taw, (650) 723 - 2781.

A Phase 1 Study of Brentuximab Vedotin Given Sequentially and Combined With Multi-Agent Chemotherapy for CD30-Positive Mature T-Cell and NK-Cell NeoplasmsNot Recruiting

The purpose of this study is to assess the safety profile of brentuximab vedotin sequentially
and in combination with multi-agent chemotherapy in front-line treatment for CD30-positive
mature T-cell and NK-cell neoplasms, including systemic anaplastic large cell lymphoma. It is
a phase 1, open-label, dose escalation study in three arms designed to define the MTD, PK,
immunogenicity, and anti-tumor activity of brentuximab vedotin in sequence and in combination
with multi-agent front-line chemotherapy.

Stanford is currently not accepting patients for this trial.For more information, please contact Sipra Choudhury, (650) 736 - 2563.

This study will enroll approximately 460 subjects, aged 55 or older, with a diagnosis of de
novo AML (Acute Myeloid Leukemia) or AML secondary to prior myelodysplastic disease or
chronic myelomonocytic leukemia (CMML), and who have achieved first Complete remission (CR)/
Complete remission with incomplete blood count recovery (CRi) following induction with or
without consolidation chemotherapy. Subjects who have previously achieved CR/CRi with a
hypomethylating agent will be excluded from the study.

Stanford is currently not accepting patients for this trial.For more information, please contact Jack Taw, 650-723-1269.

The primary objective of this study is to evaluate the effect of the addition of idelalisib
to rituximab on progression-free survival (PFS) in adults with previously treated indolent
non-Hodgkin lymphoma (iNHL).
An increased rate of deaths and serious adverse events (SAEs) among participants with
front-line chronic lymphocytic leukemia (CLL) and early-line iNHL treated with idelalisib in
combination with standard therapies was observed by the independent data monitoring committee
(DMC) during regular review of 3 Gilead Phase 3 studies. Gilead reviewed the unblinded data
and terminated this study in agreement with the DMC recommendation and in consultation with
the US Food and Drug Administration (FDA).

Stanford is currently not accepting patients for this trial.For more information, please contact Lori Richards, 650-725-8589.

Phase 1-2 of a CpG-Activated Whole Cell Vaccine Followed by Autologous Immunotransplant for MCLNot Recruiting

Mantle Cell Lymphoma is a sub-type of Non-Hodgkin's Lymphoma which is generally considered
incurable with current therapy. Our goal is to accrue 59 patients who receive an autologous
vaccine against their individual lymphoma after undergoing stem cell transplantation. Our
hope is that vaccination will prolong the time which patients will stay in remission from
their disease.

Stanford is currently not accepting patients for this trial.For more information, please contact Ami Okada, (650) 725 - 4968.

This phase II trial studies how well combination chemotherapy and pralatrexate works in
treating patients with non-Hodgkin lymphoma (NHL). Drugs used in chemotherapy work in
different ways to stop the growth of cancer cells, either by killing the cells or by stopping
them from dividing

Stanford is currently not accepting patients for this trial.For more information, please contact Sipra Choudhury, (650) 736 - 2563.

This phase I trial studies the side effects and the best dose of donor CD8+ memory T-cells in
treating patients with hematolymphoid malignancies. Giving low dose of chemotherapy before a
donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may
also stop the patient's immune system from rejecting the donor's stem cells. The donated stem
cells may replace the patient's immune cells and help destroy any remaining cancer cells
(graft-versus-cancer effects). Giving an infusion of the donor's T cells (donor lymphocyte
infusion) after the transplant may help increase this effect

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals, 650-723-0822.

This phase I/II trial studies the side effects and best dose of lenalidomide when given
together with combination chemotherapy and to see how well they work in treating patients
with newly diagnosed stage II-IV peripheral T-cell non-Hodgkin's lymphoma. Drugs used in
chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and
etoposide, work in different ways to stop the growth of cancer cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading. Lenalidomide may
stop the growth of peripheral T-cell non-Hodgkin's lymphoma by blocking the growth of new
blood vessels necessary for cancer growth. Giving combination chemotherapy with lenalidomide
may be a better treatment for peripheral T-cell non-Hodgkin's lymphoma.

This study will be conducted to assess the maximum tolerated dose (MTD) of panobinostat given
3 times a week (administered on weeks 2 and 3 of a 4 week cycle) in combination with
induction chemotherapy (idarubicin and cytarabine) in newly diagnosed patients with a
cytopathologically confirmed diagnosis of high-risk AML, and to investigate the safety of the
combination in this regimen.

Stanford is currently not accepting patients for this trial.For more information, please contact Jack Taw, (650) 723 - 2781.

A Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib Given in Combination With Bendamustine and Rituximab in Patients With Newly Diagnosed Mantle Cell LymphomaNot Recruiting

The purpose of this study is to evaluate the efficacy and safety of ibrutinib given in
combination with bendamustine and rituximab in patients 65 years of age or older with newly
diagnosed mantle cell lymphoma.

Stanford is currently not accepting patients for this trial.For more information, please contact Sipra Choudhury, 650-736-2563.

This Phase I, multicenter, first-in-human, open-label, dose-escalation study will evaluate
the safety, tolerability, and pharmacokinetics of atezolizumab (MPDL3280A) administered as
single agent to participants with locally advanced or metastatic solid malignancies or
hematologic malignancies. The study will be conducted in two cohorts: Dose-escalation cohort
and Expansion cohort.

Stanford is currently not accepting patients for this trial.For more information, please contact Maria Pitsiouni, 650-721-6977.

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer
cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies,
such as gemtuzumab, can block cancer growth in different ways. Some find cancer cells and
help kill them or carry cancer-killing substances to them. Others interfere with the ability
of cancer cells to grow and spread. Gemtuzumab may also stop the growth of promyelocytic
leukemia by blocking blood flow to the cancer. Giving gemtuzumab together with combination
chemotherapy may be more effective in treating promyelocytic leukemia.
PURPOSE: This phase II trial is studying how well giving gemtuzumab together with combination
chemotherapy works in treating patients with previously untreated promyelocytic leukemia.

Stanford is currently not accepting patients for this trial.For more information, please contact Nini Estevez, (650) 725 - 4041.

Abstract

Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkin's lymphoma. Patients are usually young and present with large mediastinal masses. There is no standard treatment, but the inadequacy of immunochemotherapy alone has resulted in routine consolidation with mediastinal radiotherapy, which has potentially serious late effects. We aimed to develop a strategy that improves the rate of cure and obviates the need for radiotherapy.We conducted a single-group, phase 2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim without radiotherapy in 51 patients with untreated primary mediastinal B-cell lymphoma. We used results from a retrospective study of DA-EPOCH-R from another center to independently verify the outcomes.The patients had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women. During a median of 5 years of follow-up, the event-free survival rate was 93%, and the overall survival rate was 97%. Among the 16 patients who were involved in the retrospective analysis at another center, over a median of 3 years of follow-up, the event-free survival rate was 100%, and no patients received radiotherapy. No late morbidity or cardiac toxic effects were found in any patients. After follow-up ranging from 10 months to 14 years, all but 2 of the 51 patients (4%) who received DA-EPOCH-R alone were in complete remission. The 2 remaining patients received radiotherapy and were disease-free at follow-up.Therapy with DA-EPOCH-R obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00001337.).

Abstract

Bendamustine is approved in the United States for relapsed indolent lymphoma. However, it has not been widely studied in mantle cell lymphoma (MCL). We retrospectively reviewed the records of all patients with MCL who were treated with bendamustine at three centers. The primary endpoint was overall response rate (ORR). Thirty patients with MCL received bendamustine, 25 for relapsed disease. After a median follow-up of 12 months, there were 15 complete responses (CRs) with an ORR of 83% (95% confidence interval [CI] 70-97%). Factors significantly associated with longer survival were achieving a CR and classical (versus blastic) variant of MCL. Grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred in 23%, 3% and 20%, respectively. There was one case of progressive multifocal leukoencephalopathy 10 months after therapy completion. Bendamustine in combination with rituximab demonstrated a high response rate in this study of patients with predominantly relapsed MCL.

Abstract

MicroRNA (miR) expression may have prognostic value for many types of cancers. However, the miR literature comprises many small studies. We systematically reviewed and synthesized the evidence.Using MEDLINE (last update December 2010), we identified English language studies that examined associations between miRs and cancer prognosis using tumor specimens for more than 10 patients during classifier development. We included studies that assessed a major clinical outcome (nodal disease, disease progression, response to therapy, metastasis, recurrence, or overall survival) in an agnostic fashion using either polymerase chain reaction or hybridized oligonucleotide microarrays.Forty-six articles presenting results on 43 studies pertaining to 20 different types of malignancy were eligible for inclusion in this review. The median study size was 65 patients (interquartile range [IQR] = 34-129), the median number of miRs assayed was 328 (IQR = 250-470), and overall survival or recurrence were the most commonly measured outcomes (30 and 19 studies, respectively). External validation was performed in 21 studies, 20 of which reported at least one nominally statistically significant result for a miR classifier. The median hazard ratio for poor outcome in externally validated studies was 2.52 (IQR = 2.26-5.40). For all classifier miRs in studies that evaluated overall survival across diverse malignancies, the miRs most frequently associated with poor outcome after accounting for differences in miR assessment due to platform type were let-7 (decreased expression in patients with cancer) and miR 21 (increased expression).MiR classifiers show promising prognostic associations with major cancer outcomes and specific miRs are consistently identified across diverse studies and platforms. These types of classifiers require careful external validation in large groups of cancer patients that have adequate protection from bias. -

Abstract

In the United States, early-stage Hodgkin's lymphoma (HL) is defined as asymptomatic stage I/II non-bulky disease. European groups stratify patients to more intense treatment by considering additional unfavorable factors, such as age, number of nodal sites, sedimentation rate, extranodal disease, and elements of the international prognostic score for advanced HL. We sought to determine the prognostic significance of these factors in patients with early-stage disease treated at Stanford University Medical Center.This study was a retrospective analysis of 101 patients treated with abbreviated Stanford V chemotherapy (8 weeks) and 30-Gy (n=84 patients) or 20-Gy (n=17 patients) radiotherapy to involved sites. Outcomes were assessed after applying European risk factors.At a median follow-up of 8.5 years, freedom from progression (FFP) and overall survival (OS) rates were 94% and 97%, respectively. From 33% to 60% of our patients were unfavorable per European criteria (i.e., German Hodgkin Study Group [GHSG], n=55%; European Organization for Research and Treatment of Cancer, n=33%; and Groupe d'Etudes des Lymphomes de l'Adulte, n=61%). Differences in FFP rates between favorable and unfavorable patients were significant only for GHSG criteria (p=0.02) with there were no differences in OS rates for any criteria. Five of 6 patients who relapsed were successfully salvaged.The majority of our patients deemed unfavorable had an excellent outcome despite undergoing a significantly abbreviated regimen. Application of factors used by the GHSG defined a less favorable subset for FFP but with no impact on OS. As therapy for early-stage disease moves to further reductions in therapy, these factors take on added importance in the interpretation of current trial results and design of future studies.

Abstract

Over the past three decades, due to the recognition of late effects related to high-dose extended field radiotherapy and heavy alkylator chemotherapy, combined modality therapy with abbreviated chemotherapy and limited field radiotherapy has emerged as the standard of care for early stage Hodgkin lymphoma, with cure rates in excess of 80%. Currently, however, controversy remains over identifying the most appropriate criteria to risk-stratify patients with early stage disease, so that those with a favorable prognosis receive limited treatment without compromising cure rates and those with unfavorable risk receive more intensified therapy. The optimal risk stratification system remains unclear, with variable definitions of favorable and unfavorable disease used by research groups in North America and Europe. Thus, comparison of clinical trial results has been challenging, and additional controversies persist regarding optimal chemotherapy regimens, duration of therapy, and the role of radiotherapy. Investigations are ongoing to assess the potential of functional imaging and biomarkers as tools for risk stratification. The collective goal is to further refine current stratification strategies to allow for an individualized, risk-adapted treatment approach that minimizes long-term late effects without compromising high cure rates.

Abstract

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subset of Hodgkin lymphoma that is distinct from classical Hodgkin lymphoma (cHL). The unique malignant 'popcorn' cells express the B-cell antigen CD20 and lack expression of the cHL markers CD15 and CD30. Traditionally, NLPHL has been included with cHL in clinical trials with excellent prognosis reported in several series. The reliable expression of CD20 has led to the evaluation of the chimeric monoclonal anti-CD20 antibody rituximab in several recent trials.Three series have reported the efficacy of 4 weekly doses of rituximab in all stages of NLPHL, both in the treatment-naive and relapsed settings. Emerging data also suggest that longer courses of antibody therapy may improve the duration of response.Rituximab appears to offer a nonchemotherapy-based effective treatment option, which is well tolerated. Ongoing studies are required to further define the optimal patient population who may benefit from rituximab and evaluate its role in maintenance as well as in combination with radiotherapy and chemotherapy.

Abstract

To correlate [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) status after chemotherapy, but before radiation, with outcome in patients treated with the Stanford V regimen.We analyzed retrospectively 81 patients with Hodgkin's disease who had serial [(18)F]FDG-PET scans performed at baseline and again at the completion of Stanford V chemotherapy, before planned radiotherapy. Patients with favorable stage I/II (nonbulky mediastinal disease) and those with bulky mediastinal disease or stage III/IV were scanned after 8 and 12 weeks of chemotherapy, respectively. Radiotherapy fields were determined before starting chemotherapy based on baseline computed tomography scans.After chemotherapy, six of 81 patients had residual [(18)F]FDG-PET-positive sites, all in sites for which radiotherapy was planned. Four of the six patients with positive [(18)F]FDG-PET scans after chemotherapy experienced relapse compared with just three of 75 patients with negative [(18)F]FDG-PET scans. At a median follow-up of 4 years, the freedom from progression (FFP) was 96% in postchemotherapy [(18)F]FDG-PET-negative patients versus 33% in [(18)F]FDG-PET-positive patients (P < .0003). In a bivariate Cox model, [(18)F]FDG-PET positivity after chemotherapy remained a highly significant predictor of progression-free survival even after controlling for bulky disease and International Prognostic Score more than 2.These data indicate that PET status after chemotherapy is strongly predictive of FFP with the Stanford V regimen despite the use of consolidative radiotherapy. These results have implications for the design of clinical trials adapted to functional imaging.

Transcription arrest at an abasic site in the transcribed strand of template DNACHEMICAL RESEARCH IN TOXICOLOGYTornaletti, S., Maeda, L. S., Hanawalt, P. C.2006; 19 (9): 1215-1220

Abstract

A dedicated excision repair pathway, termed transcription-coupled repair (TCR), targets the removal of DNA lesions from transcribed strands of expressed genes. Transcription arrest at the site of the lesion has been proposed as the first step for initiation of TCR. In support of this model, a strong correlation between arrest of transcription by a lesion in vitro and TCR of that lesion in vivo has been found in most cases analyzed. TCR has been reported for oxidative DNA damage; however, very little is known about how frequently occurring and spontaneous DNA damage, such as depurination and base deamination, affects progression of the transcription complex. We have previously determined that the oxidative lesion, thymine glycol, is a significant block to transcription by T7 RNA polymerase (T7 RNAP) but has no detectable effect on transcription by RNA polymerase II (RNAP II) in a reconstituted system with all of the required factors. Another oxidative lesion, 8-oxoguanine, only slightly blocked T7 RNAP and caused RNAP II to briefly pause at the lesion before bypassing it. Because an abasic site is an intermediate in the repair of oxidative damage, it was of interest to learn whether it arrested transcription. Using in vitro transcription assays and substrates containing a specifically positioned lesion, we found that an abasic site in the transcribed strand is a 60% block to transcription by T7 RNAP but nearly a complete block to transcription by mammalian RNAP II. An abasic site in the nontranscribed strand did not block either polymerase. Our results clearly indicate that an abasic site is a much stronger block to transcription than either a thymine glycol or an 8-oxoguanine. Because the predominant model for TCR postulates that only lesions that block RNAP will be subject to TCR, our findings suggest that the abasic site may be sufficient to initiate TCR in vivo.

Abstract

2-Deoxyribonolactone (dL) is an oxidized abasic site in DNA that can be induced by gamma-radiolysis, ultraviolet irradiation, and numerous antitumor drugs. Although this lesion is incised by AP endonucleases, suggesting a base-excision repair mechanism for dL removal, subsequent excision and repair synthesis by DNA polymerase beta is inhibited due to accumulation of a protein-DNA cross-link. This raises the possibility that additional repair pathways might be required to eliminate dL from the genome. Transcription-coupled repair (TCR) is a pathway of excision repair specific to DNA lesions present in transcribed strands of expressed genes. A current model proposes that transcription arrest at the site of DNA damage is required to initiate TCR. In support of this model, a strong correlation between transcription arrest by a lesion in vitro and TCR of the lesion in vivo has been found in most cases analyzed. To assess whether dL might be subject to TCR, we have studied the behavior of bacteriophage T3 and T7 RNA polymerases (T3RNAP, T7RNAP) and of mammalian RNA polymerase II (RNAPII) when they encounter a dL lesion or its "caged" precursor located either in the transcribed or in the nontranscribed strand of template DNA. DNA plasmids containing a specifically located dL downstream of the T3, T7 promoter or the Adenovirus major late promoter were constructed and used for in vitro transcription with purified proteins. We found that both dL and its caged precursor located in the transcribed strand represented a complete block to transcription by T3- and T7RNAP. Similarly, they caused more than 90% arrest when transcription was carried out with mammalian RNAPII. Furthermore, RNAPII complexes arrested at dL were subject to the transcript cleavage reaction mediated by elongation factor TFIIS, indicating that these complexes were stable. A dL in the nontranscribed strand did not block either polymerase.

Abstract

8-Oxoguanine (8-oxoG) is a major oxidative lesion produced in DNA by normal cellular metabolism or after exposure to exogenous sources such as ionizing radiation. Persistence of this lesion in DNA causes G to T transversions, with deleterious consequences for the cell. As a result, several repair processes have evolved to remove this lesion from the genome. It has been reported that 8-oxoG is subject to transcription-coupled repair (TCR), a process dedicated to removal of lesions from transcribed strands of expressed genes. A current model assumes that RNA polymerase arrest at the site of the lesion is required for initiation of TCR. As a first step to understand how TCR of 8-oxoG occurs, we have studied the effect of 8-oxoG on transcription elongation by T7 RNA polymerase (T7 RNAP) and rat liver RNA polymerase II (RNAPII). We have utilized an in vitro transcription system with purified RNA polymerase and initiation factors, and substrates containing a single 8-oxoG in the transcribed or in the non-transcribed strand downstream of the T7 promoter or the Adenovirus major late promoter. We found that 8-oxoG only slightly inhibited T7 RNAP transcription, with a readthrough frequency of up to 95%. Similarly, this lesion only transiently blocked transcription by RNAPII. However, changes in nucleotide concentration affected the extent of RNAPII blockage at the 8-oxoG. When this lesion was positioned in the non-transcribed strand, complete lesion bypass was observed with either polymerase. Binding of the Saccharomyces cerevisiae MSH2-MSH6 complex to 8-oxoG containing substrates did not increase the frequency of RNAPII arrest at the site of the lesion, suggesting that this complex was displaced by the elongating polymerase. These results are discussed in the context of possible models for TCR.

Abstract

Thymine glycols are formed in DNA by exposure to ionizing radiation or oxidative stress. Although these lesions are repaired by the base excision repair pathway, they have been shown also to be subject to transcription-coupled repair. A current model for transcription-coupled repair proposes that RNA polymerase II arrested at a DNA lesion provides a signal for recruitment of the repair enzymes to the lesion site. Here we report the effect of thymine glycol on transcription elongation by T7 RNA polymerase and RNA polymerase II from rat liver. DNA substrates containing a single thymine glycol located either in the transcribed or nontranscribed strand were used to carry out in vitro transcription. We found that thymine glycol in the transcribed strand blocked transcription elongation by T7 RNA polymerase approximately 50% of the time but did not block RNA polymerase II. Thymine glycol in the nontranscribed strand did not affect transcription by either polymerase. These results suggest that arrest of RNA polymerase elongation by thymine glycol is not necessary for transcription-coupled repair of this lesion. Additional factors that recognize and bind thymine glycol in DNA may be required to ensure RNA polymerase arrest and the initiation of transcription-coupled repair in vivo.